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Abstract

Background

Little is known about the long-term success of non-drug therapies for treating dementia,
especially whether the effects are sustained after therapy ends. Here, we examined
the effects of a one-year multimodal therapy 10 months after patients completed the
therapy.

Methods

This randomised, controlled, single-blind, longitudinal trial involved 61 patients
(catamnesis: n = 52) with primary degenerative dementia in five nursing homes in Bavaria,
Germany. The highly standardised intervention, MAKS, consisted of motor stimulation,
practice of activities of daily living (ADLs), and cognitive stimulation. Each group
of 10 patients was treated for 2 h, 6 days a week for 12 months. Control patients
received standard nursing home care. At baseline, at the end of therapy (month 12),
and 10 months thereafter (month 22), cognitive functioning was assessed using the
cognitive subscale of the Alzheimer’s Disease Assessment Scale, and the ability to
perform ADLs was assessed using the Erlangen Test of Activities of Daily Living.

Results

During the therapy phase, the MAKS patients maintained their cognitive function and
ability to carry out ADLs. After the end of therapy, both the control and the MAKS
groups deteriorated in both their cognitive function (control, p = 0.02; MAKS, p < 0.001)
and their ability to carry out ADLs (control, p < 0.001; MAKS, p = 0.001). However,
in a confound-adjusted multiple regression model, the ability of the MAKS group to
perform ADLs remained significantly higher than that of the control group even 10
months after the end of therapy (H0: βMAKS + βMAKS month 22 = 0; χ2 = 3.8568, p = 0.0496). Cohen’s d for the difference between the two groups in ADLs
and cognitive abilities 10 months after the end of therapy was 0.40 and 0.22, respectively.

Conclusions

A multimodal non-drug therapy of dementia resulted in stabilisation of the ability
to perform ADLs, even beyond the end of therapy. To prevent functional decline for
as long as possible, therapy should be performed continuously until the benefit for
the patient ends. Follow-up studies on larger numbers of patients are needed to definitively
confirm these results.

Trial registration

Keywords:

Dementia; Non-drug-therapy; RCT; Follow-up study; Nursing home

Background

Alzheimer’s dementia has been treated with drug therapy, non-drug therapy, and a combination
of the two therapy types. In recent years, some studies have demonstrated the efficacy
of non-drug therapy
[1,2]. Unimodal interventions usually target cognition or the neuropsychological symptoms
of dementia, and most available data are used to assess the efficacy of cognitive
approaches
[3]. However, the greatest effects of non-drug therapies in the treatment of Alzheimer’s
dementia are achieved with multimodal therapy
[1,4,5]. Cognitive training combined with treatment with acetylcholinesterase inhibitors
has also been used and often brings better results than drug therapy alone
[6,7], but intensive non-drug therapies alone also appear to be superior to drug therapy
alone
[7].

Little is known about the sustainability of any of these therapeutic effects. Whereas
it would be expected that the cognitive performance of Alzheimer patients who respond
to drug therapy will inevitably deteriorate when the medication is withdrawn
[8,9], preliminary evidence indicates that non-drug therapies may result in greater sustainability
of cognition and the ability to carry out activities of daily living (ADLs)
[10,11]. Theoretically, this can be explained in that non-drug therapies strengthen abilities
that the dementia patient can apply in everyday life and thus lead to a self-strengthening
or more-or-less continued self-training. Yet no high-quality methodological studies
have addressed this assumption. In a recent Cochrane review up to the end of 2011
[12] on the efficacy of cognitive training, 15 randomised controlled trials (RCTs) met
the criteria for inclusion in the review. Only 4 of these studies examined the efficacy
of the intervention after the end of therapy—3 during the first 3 months, and 1 at
10 months after the end of therapy. In the last study
[6], neither cognition nor the ability to perform ADLs differed significantly between
the therapy and control groups 10 months after the end of therapy [cognitive subscale
of the Alzheimer’s Disease Assessment Scale (ADAS-cog): p = 0.66, SMD 0.12 (−0.41;
0.66); Texas Functional Living Scale: p = 0.12, SMD 0.43 (−0.30; 0.97)]. In addition
to the 8-week cognitive training of the therapy group, all patients received the acetylcholinesterase
inhibitor donepezil for the entire study period. In the re-analysis of the 3 other
studies that examined the efficacy 1 to 3 months after the end of therapy, a significant
effect on cognition was found (p = 0.05)
[12]. These 3 studies did not examine ADLs. Further high-quality methodological studies
of the sustainability of non-drug therapies are needed, not only because of their
importance for cost savings in the health system
[13].

In a blinded RCT design, we have demonstrated the efficacy of our multimodal activation
therapy developed for institutionalised patients
[14] with respect to cognition and the ability to carry out ADLs after a 12-month therapy
[5,15]. In the subsequent follow-up study reported here in which we address the sustainability
of the therapeutic effects, all of the patients still living 10 months after the end
of therapy were re-examined using the same instruments.

Methods

Study design

Ten months after the end of our randomised, controlled, single-blind longitudinal
trial of a multicomponent, non-pharmacological group therapy known as MAKS, we examined
the efficacy of the therapy with dementia patients in five German nursing homes
[5]. The MAKS therapy phase lasted 12 months, beginning in December 2008 and ending in
December 2009. During this period, the MAKS group received 2h multimodal therapy 6
days a week, whereas a control group received the standard nursing home care. Both
groups were examined with respect to cognitive function and their ability to perform
ADLs prior to starting therapy (baseline), at the time therapy ended (month 12), and
10 months after the end of therapy (month 22).

Sample

Ninety-eight patients included in the original study fulfilled the following inclusion
criteria: presence of primary degenerative dementia according to ICD-10 (F00, F03,
or G30) and as confirmed by the attending physician; fewer than 24 points on the Mini-Mental
State Examination (MMSE)
[16]; and written informed consent of the patient or, when necessary, the patient’s legal
guardian prior to baseline. This means that most of the patients are supposed to suffer
from Alzheimer’s disease or a mixed form of Alzheimer/vascular dementia. Patients
with pure vascular dementias were excluded. Of the approximately 400 residents who
were positively screened for dementia, only 47 had to be excluded because of non-degenerative
dementia according to the attending physician (see Figure
1). The sample therefore represents about 90% of the nursing home residents with cognitive
deficits. The form sheet, all legal conditions, and the study design were examined
by the Ethics Committee of the Medical Faculty of the University of Erlangen. Approval
was granted on 10 July 2008 (Registration Number 3232). Exclusion criteria were as
follows: vascular (F01) or secondary (F02) dementia according to ICD-10; the presence
of other neurological/psychiatric disease(s) that could explain the patient’s decline
in cognitive function; very high nursing care needs (i.e. care level 3, which is the
highest level of the three-level scale currently used to determine eligibility for
nursing care benefits in Germany); deafness; or blindness. Taking medication of any
type did not affect inclusion or exclusion in our study (see Table
1 for medication taken). Of the 98 patients included, 35 met the dropout criteria during
the intervention period, and 2 had to be excluded because of an incorrect diagnosis
(i.e. n = 61 at month 12). Nine patients died in the 10 months between the end of
therapy and the follow-up study. Hence, the follow-up analysis comprised 52 patients—22
in the control group and 30 in the MAKS intervention group (Figure
1).

Table 1.Characteristics of the patients participating through the follow-up analysis

Patients

The number of patients analysed consisted of the number eligible at each time point
(Figure
1). All patients who completed 12 months of either the MAKS therapy or the control
group (standard nursing home care) were examined at the end of the therapy at month
12 (n = 61), and those who were still alive 10 months after the end of therapy were
examined in the follow-up analysis at month 22 (n = 52). The patients who completed
the study did not differ at baseline from those that were excluded in terms of age
(t-test: p = 0.58), cognition (MMSE: p = 0.27; ADAS-cog: p = 0.14), and ability to
carry out ADLs (Erlangen Test of Activities of Daily Living; E-ADL test: p = 0.08).

The characteristics of the 52 patients who completed the follow-up analysis are summarised
in Table
1. Patients were on average 84 years old; 83% were female. Only 6 of the 52 patients
were taking anti-dementia drugs; 3 were in the control group, and 3 were in the MAKS
group. The MMSE score was on average 15 points.

Treatment conditions

MAKS is a multicomponent group therapy consisting of tasks organised into three categories—motor
stimulation (M), ADLs (A), and cognition (K)—preceded by a short introduction consisting
of what we called a spiritual element (S). Each daily session began with this introduction,
which lasted approximately 10 min and was designed to help the dementia patients feel
part of the group. This was followed by about 30 min of motor exercises. After a 10-min
break, the patients spent approximately 30 min completing a variety of cognitive tasks.
This was followed by about 40 min of ADLs [for further information, see
[5]].

The members of the control group received the standard care offered in each nursing
home and were free to participate in any of the regular, non-MAKS activities offered
at the nursing home. Patients in the control group participated in an average of two
of these non-MAKS activities per week. Also, patients in the MAKS group were free
to take part in these non-MAKS activities in addition to MAKS and did so once a week
on average. The study did not interfere in any way with the patients’ existing pharmacological
treatment or nursing care.

Implementation of treatment

MAKS therapy was conducted in each nursing home by two therapists and one aide from
Monday to Saturday from 9:30 am to 11:30 am for 12 months. The therapists were registered
geriatric nurses. Each therapy group consisted of 10 dementia patients. Therapists
and aides received a standardised handbook from the central study site describing
in detail the steps to be taken on each day of therapy
[14]. This guaranteed that the same tasks would be performed on any given day at each
nursing home [for further information, see
[5]].

Instruments and data recording

The cognitive and ADL-abilities of the patients were recorded by independent evaluators,
who were blinded to treatment allocation and were not part of the nursing home staff.
The patients were evaluated before the therapy commenced (baseline), at the end of
the 12-month therapy (month 12), and 10 months after completion of the therapy (month
22), with all patients having the standard nursing home care during this latter period.
Data were pseudonymised and submitted to the central study site.

The ability to carry out ADLs was measured using the E-ADL test
[18]. This is a performance test of fundamental abilities of daily living under standardised
conditions and includes pouring a drink, cutting a piece of bread, opening a little
cupboard, washing one’s hands, and tying a bow. The range is from 0 to 30, with higher
scores indicating a greater ability to carry out the activities (α = 0.77).

Study coordinators recorded each patient’s age, gender, educational attainment, family
status, and nursing care needs at baseline. The nursing staff rated symptoms of depression
among the patients at baseline using the mood subscale of the Nurses’ Observation
Scale of Geriatric Patients (NOSGER)
[19] (test-retest reliability: 0.85; correlation with the Geriatric Depression Scale:
rS = 0.63).

We also calculated the effect of any previous medical diagnoses on the mortality rate
using the Charlson comorbidity index
[20]. Potential bias resulting from pharmacological interventions was accounted for by
using a medication score (sedative/stimulating effect of all medication) (see Table
1).

Statistical analysis

We statistically analysed the data of all patients who completed the primary intervention
period of 12 months either in the MAKS group or in the control group (n = 61). In
the analysis of the follow-up data, we made attempts to record outcome variables for
all patients who completed the intervention period and who were still alive 10 months
after the end of therapy (n = 52). If more than 20% of the items on the ADAS-cog subscale
or the E-ADL test were missing for any given patient (e.g. because of his or her refusal
to complete the test), the score was calculated according to the expectation-maximum
(EM) algorithm. Under these conditions, imputation at the 10-month follow-up was necessary
in 4 cases. The scores for patients who died during the 10-month interim period without
therapy (n = 9) were not imputed. The number of patients eligible for the analysis
in the multiple regression models was 61 at the end of the therapy (at month 12) and
52 after the 10 months following the therapy (at month 22).

To describe the course, t-tests for dependent samples were calculated for both groups
for the two time periods. The first period was the 12-month therapy period (from baseline
to month 12), and the second period was the 10-month interim without therapy between
evaluations (from month 12 to month 22). Model diagnostics of the differences revealed
no deviation from a normal distribution. Cohen’s d with pooled standard deviation
[21] was calculated as the measure of effect size.

Differences between the groups were calculated with multiple analyses to adjust for
possible confounders; multiple linear mixed models were computed. We computed two
separate models, one for the E-ADL test score and one for the ADAS-cog score. For
the analysis, we adjusted the score at months 12 and 22 for the baseline values (score
at month 12 – baseline score, and score at month 22 – baseline score). We then built
a variable that contains both measurements for each patient (where available) and
used another variable to reflect the time of measurement (“repeated measurements”).
We included the following independent variables: intervention group (MAKS vs. control),
observation time (month 12 vs. month 22), age of the patient, medication score, NOSGER
subscale mood, anti-dementia medication, and the interaction of the intervention group
and observation time to account for possible changes of the group effect over time.
The “nursing home” entered the model as a random effect. Model diagnostics revealed
no substantial deviation from the model assumptions.

In a sensitivity analysis, we additionally included a random slope for time to account
for possible non-systematic variations over time. For the analyses, we used the statistical
software packages R
[22] and SPSS
[23]. P-values smaller than 0.05 indicate significant effects.

Figure 2.Median E-ADL test values over time. Median E-ADL test values in the groups MAKS and control over time together with the
corresponding notched boxplots. Lower scores indicate greater deficits. Boxplots represent
the distribution of raw data values. Non-overlapping notches are a (rough) indicator
of significantly different medians [see
[28].

Figure 3.Median ADAS-cog values over time. Median ADAS-cog values in the MAKS and control groups over time together with the
corresponding notched boxplots. Higher scores indicate greater deficits. Boxplots
represent the distribution of raw data values. Non-overlapping notches are a (rough)
indicator of significantly different medians
[28].

In the confound-adjusted multiple regression model with the random effect of “nursing
home” (see Additional file
1), the E-ADL test score of the MAKS group remained significantly higher than that
of the control group even 10 months after the end of therapy (H0: βMAKS + βMAKS month 22 = 0; χ2 = 3.86, p = 0.0496). The effect of therapy on the ability to carry out ADLs over
time was not only sustainable but even increased slightly over time after the end
of the MAKS therapy, as can be seen in the widening of the solid lines in Figure
4.

Figure 4.Estimated changes of E-ADL test score compared to baseline using a random effects
model. Higher scores indicate better abilities to perform ADLs. The solid lines represent
effect estimates from a model with an interaction term for time and group, i.e. where
the group effect can change over time. The dashed lines indicate a model without interaction.
In this case, the group effect is forced to stay constant (as can be seen from the
parallel dashed lines from month 12 to month 22).

In a sensitivity analysis, we additionally adjusted for a potential auto-correlation
between the time points and thus included a random slope for time. In this case, the
effect of MAKS therapy 10 months after the end of therapy was no longer significant
(χ2 = 2.49, p = 0.116). Despite the lack of a significant difference in this case, the
effect estimates revealed the same structure as depicted in Figure
4, i.e. the effects of the model with the interaction indicate that the effect of therapy
(month 12) was not only preserved but had a slight tendency to become even more pronounced
10 months after the therapy (month 22).

As for the ADLs, we used a confound-adjusted model with a random effect of “nursing
home” to evaluate the long-term effect of MAKS therapy on cognition (ADAS-cog; see
Additional file
1). We did not observe a lasting effect of MAKS therapy on ADAS-cog (H0: βMAKS + βMAKS month 22 = 0; χ2 = 1.15, p = 0.282). One can even deduce from Figure
5 that the groups were slowly converging.

Figure 5.Estimated changes of ADAS-cog compared to baseline using a random effects model. Higher scores indicate greater deficits. The solid lines represent effect estimates
from a model with an interaction term for time and group, i.e. where the group effect
can change over time. The dashed lines indicate a model without interaction. In this
case, the group effect is forced to stay constant (as can be seen from the parallel,
dashed lines from month 12 to month 22).

The sensitivity analysis with an additional random slope of time did not change the
result (MAKS vs. control at month 22: χ2 = 0.88, p = 0.347).

Discussion

The present study addressed whether the positive effects on cognition and the ability
to carry out ADLs of a 12-month multimodal therapy of dementia patients are sustainable
10 months after the end of therapy. This study is thus one of the first RCTs to systematically
examine the sustainability of the effects of a non-drug therapy in dementia patients.
Our results using a confound-adjusted multiple regression model indicated that the
positive effects of the group therapy (i.e. therapy group vs. control group) on the
ability to carry out ADLs were indeed sustainable. This effect was still existent
but no longer statistically significant when controlled for a random subject-specific
slope. Such a finding is unique in the literature. To date, only two randomised studies
have addressed the sustainability of non-drug therapy procedures on cognition and
the ability to carry out ADLs, but in combination with cholinesterase inhibitors.

In a recent study on dementia patients living at home, Giordano et al.
[24] showed that the success of therapy combining cholinesterase inhibitors and a 3-week
Reality Orientation Training (ROT) could still be demonstrated 2 months after the
active intervention phase as long as family members continued the ROT. Control patients
were treated only with cholinesterase inhibitors. The patients of the therapy group
profited, however, only in the cognitive area; effects on their ability to carry out
activities of daily living were never observed. Moreover, therapy was never withdrawn
as medication was maintained in both the ROT and control groups, and caregivers of
the test group were asked to continue ROT at home, even if this potentially occurred
in a less systematic form. One problem that this study had is the short time frame,
as even placebo effects can last up to 9 months as Ito et al.
[25] demonstrated in a meta-analysis.

Chapman et al.
[6] studied the efficacy of a combination therapy consisting of donepezil and cognitive
stimulation therapy in a controlled randomised study of 54 dementia patients. The
control group received donepezil alone. The parameters were cognition, ability to
carry out ADLs, and neuropsychiatric symptoms. The therapy was conducted once a week
for 2 months. With the two scales used (ADAS-cog and Texas Functional Living Scale
TFLS), which are comparable to those of our study, the authors found a significant
decline in abilities in both the test and control groups over the course of a year.
No effects on cognition or the ability to perform ADLs could be demonstrated at the
end of therapy or 10 months after ending therapy. However, an advantage of the combined
therapy was found in the MMSE and some subscales of the Neuropsychiatric Inventory
(NPI) 10 months after the end of therapy. As effects of pharmacological treatment
have been shown elsewhere to last less than 12 months
[25], the differences between the treatment and control groups are more likely related
to the cognitive stimulation. The lack of effects on the ADAS-cog and the TFLS of
this therapy may be attributable to its low intensity (8 sessions over 2 months),
which is considerably less intensive than our MAKS therapy (about 300 sessions over
12 months). Other studies examining the sustainability of non-drug therapy procedures
have usually addressed the neuropsychological symptoms of dementia, such as mood and
behaviour e.g.
[26,27] or are of limited reliability due to the small number of patients
[10,11].

In the main analysis, we found a long-term effect of the MAKS therapy on the ability
to carry out ADLs but not on cognition. Future studies should test whether ADL training
will preserve the self-reliance of the participating home residents more than that
of the control group. This in turn would mean that ADLs are performed independently
to a greater extent and are thus automatically trained further. By contrast, the long-term
effect of MAKS therapy on cognitive functions is much lower. Here, the difference
between the control group and therapy group was smaller 10 months after the end of
therapy, and the effect of the therapy was no longer demonstrable in multivariate
analyses. Compared to a strictly pharmaceutical therapy, a non-drug therapy thus appears
to offer the potential of an effect that promotes independence in everyday living
that lasts beyond the term of therapy, even if the positive effect on cognitive functions
did not continue after therapy ended. Because the cognitive abilities as well as ADLs
abilities were preserved in the MAKS group during therapy, a continuous therapy could
perhaps stabilise both abilities even longer.

A limitation of the present study is the number of patients. After 22 months, only
a relatively small sample number of patients remained (n = 52), owing in part to the
high mortality rate in the age spectrum examined. The small number of cases is probably
also the reason why the model in the sensitivity analysis with a random slope did
not attain significance for the ability to carry out ADLs, especially since the variation
of the measured E-ADL test scores increased over time (see Figure
2). Also, results are valid only for patients with degenerative dementias such as Alzheimer’s
dementia or dementia of the mixed form. Effects on persons with vascular dementia
were not examined. Another limitation might be the use of the ADAS-cog as the outcome
instrument for cognition. The ADAS-cog does not have parallel versions for test-retest
settings; stabilisation might therefore be due to learning effects rather than due
to therapy. However, this effect would be the same in the control and therapy groups.
Thus, differences between the groups cannot be explained by learning effects. Further
studies with a considerably larger number of patients, an extended follow-up period,
and more sensitive test items are thus necessary to verify the results shown here.

One strength of the study is the strict RCT design used during the therapy phase.
To our knowledge, our study is thus the first to examine the sustainability of an
exclusively non-drug therapy of dementia after completion of the active therapy phase.
Our method is also notable in that all dependent variables were recorded blindly by
testing and not, as is often the case, by using outside assessment.

Conclusions

Our intensive multimodal therapy was elsewhere shown to be effective in the treatment
of dementia with regard to both cognitive functioning and the ability to perform ADLs
with greater effect sizes for patients with mild to moderate dementia
[5]. This study of the long-term effects of a non-drug therapy showed that upon withdrawal
of non-drug therapy, the ability to perform ADLs—as compared to cognitive functioning—tended
to be more focused on “self-preservation”. Hence, intensive multimodal therapy should
be started as early as possible to maintain the abilities still present in the dementia
patient. It is also especially important to apply the therapy continuously to retain
for as long as possible not only the ADL-abilities but also the cognitive functions,
and thus to retain the independence of people with dementia. Future research on this
topic including a larger sample size, even longer follow-up periods, and perhaps different
outcome measurements should be performed to support the findings.

Competing interests

The authors declare that they have no competing interests. The research reported was
funded by the German Ministry of Health (LT-Demenz-44-059), which had no role in designing
or conducting the study; in collecting, analysing, or interpreting the data; or in
preparing, reviewing, or approving the manuscript. The researchers acted fully independently
of the sponsor.

Authors’ contributions

All authors had full access to all of the data in the study. EG designed the study
concept and obtained funding. KL and BH provided administrative, technical, or material
support. KL and EG acquired data. All authors statistically analysed and interpreted
the data, critically revised the manuscript for important intellectual content, and
read and approved the final manuscript.

Acknowledgements

We thank all individuals who contributed to this study, especially the patients, the
directors of the participating nursing homes, the nursing staff, the therapists, and
the evaluators. We are grateful to the German Ministry of Health for funding. We thank
Friedrich Mueller, former head of the Elderly Care Department of Diakonie Neuendettelsau,
who took part in designing the study and collaborated in conducting the study; Dr.
Christine Fiedler, PD Dr. Richard Mahlberg, Hans-Dieter Mückschel, and PD Dr. Martin
Radespiel-Troeger, who acted as Data Monitoring and Safety Board members and who supervised
the study. We thank Dr. Jane Zagorski for critically editing the English language
of the manuscript.

NICE [National Institute for Health and Clinical Excellence] London: National Institute for Health and Clinical Excellence, Social Care Institute
for Excellence: NICE clinical guideline; 2007:1-56.
[Dementia: Supporting people with dementia and their carers in health and social care]